Vehicle composition containing 1-substituted azacycloalkan-2-ones

ABSTRACT

Compositions useful for carrying physiologically active agents such as therapeutic agents through skin and other body membranes comprising the agent and an effective, non-toxic amount of a compound having the structural formula ##STR1## wherein R&#39; is H or a lower alkyl group, m is 3-7, N is 0-17 and R is --CH 3 , phenyl or substituted phenyl or ##STR2## with the proviso that if m is 3 and R is --CH 3 , then n is not 0-6.

This is a division of application Ser. No. 725,490, abandoned, filedOct. 28, 1978, which in turn is a continuation-in-part of applicationSer. No. 588,247 filed June 19, 1975, now U.S. Pat. No. 3,989,816.

BACKGROUND OF THE INVENTION

Many physiologically active agents are best applied topically to obtaindesirable results. Topical application, as contrasted to systemicapplication, largely avoids side effects of the agents and permits highlocal concentrations of the agents.

The greatest problem in applying physiologically active agents topicallyis that the skin is such an effective barrier to penetration. Theepidermis of the skin has an exterior layer of dead cells called thestratum corneum which is tightly compacted and oily and which providesan effective barrier against gaseous, solid or liquid chemical agents,whether used alone or in water or oil solutions. If a physiologicallyactive agent penetrates the stratum corneum, it can readily pass throughthe basal layer of the epidermis and into the dermis.

Although the effectiveness of the stratum corneum as a barrier providesgreat protection, it also frustrates efforts to apply beneficial agentsdirectly to local areas of the body. The inability of physiologicallyactive agents to penetrate the stratum corneum prevents their effectiveuse to treat such conditions as inflamation, acne, psoriasis, herpessimplex, eczema, infections due to fungus, virus or othermicroorganisms, or other disorders or conditions of the skin or mucousmembranes, or of conditions beneath the exterior surface of the skin ormucous membranes. The stratum corneum also prevents the skin fromabsorbing and retaining cosmetic-type materials such as sunscreens,perfumes, mosquito repellants and the like.

Physiologically active agents may be applied to locally affected partsof the body through the vehicle system described herein. Vehicles suchas USP cold cream, ethanol and various ointments, oils, solvents, andemulsions have been used heretofore to apply physiologically activeingredients locally. Most such vehicles are not effective to carrysignificant amounts of physiologically active agents through the skin.One such vehicle is dimethyl sulfoxide, which is described in U.S. Pat.No. 3,551,554. In this description, the term "animal" includes humanbeings as well as other forms of animal life, and especiallydomesticated animals and pets.

The 1-lower alkyl substituted azacyclopentan-2-ones having 1-4 carbonatoms are known to moderately enhance percutaneous absorption ofchemicals, e.g., drugs. It would be desirable to obtain the same orhigher level of percutaneous absorption with substantially lowerconcentrations of the penetration-enhancing compound.

SUMMARY OF THE INVENTION

This invention relates to compositions for carrying physiologicallyactive agents through body membranes such as skin and for retainingthese agents in body tissues. More specifically, the invention relatesto compositions useful in topically administering a physiologicallyactive agent to a human or animal comprising the agent and an effective,non-toxic amount of a compound having the structural formula ##STR3##

where R' is H or a lower alkyl group having 1-4 carbon atoms, m is 3-7,n is 0-17, and R is --CH₃, ##STR4## where R"=H or Halogen and R' has thesame meaning as above, with the proviso that if m=3 and R=--CH₃ then nis not 0-6. In one preferred embodiment, R' is H, m is 3-7, R is --CH₃or C₆ H₅ and n is 0-11.

In another the preferred embodiment, R' is H, m, is 5-7 and R is CH₃ andn is 0-11. The preferred compound is 1-n-dodecylazacycloheptan-2-one.

It has been found that the physiologically active agents are carriedthrough body membranes by the claimed vehicles and are retained in bodytissue.

The invention further relates to vehicles themselves and their method ofmaking.

DETAILED DESCRIPTION OF THE INVENTION

The claimed 1-substituted azacycloalkan-2-ones are made by methodsdescribed below and as further described in the Examples. Typicalexamples of compound included in the foregoing formula are thefollowing:

1-n-hexylazacyclopentan-2-one

1-n-heptylazacyclopentan-2-one

1-n-octylazacyclopentan-2-one

1-n-nonylazacyclopentan-2-one

1-n-decylazacyclopentan-2-one

1-n-dodecylazacyclopentan-2-one

1-methylazacycloheptan-2-one

1-n-propylazacycloheptan-2-one

1-n-butylazacycloheptan-2-one

1-n-pentylazacycloheptan-2-one

1-n-hexylazacycloheptan-2-one

1-n-heptylazacycloheptan-2-one

1-n-octylazacycloheptan-2-one

1-n-nonylazacycloheptan-2-one

1-n-decylazacycloheptan-2-one

1-n-butylazacyclononan-2-one

1-n-octylazacyclononan-2-one

1-phenylazacyclopentan-2-one

1-benzylazacyclopentan-2-one

1-(2-chlorophenyl)azacyclopentan-2-one

1,3-Bis-(1-azacyclopentan-2-onyl)propane

1,6-Bis-(1-azacyclopentan-2-onyl)hexane

The compounds covered by the general formula may be prepared by treatingazacycloalkan-2-one with an alkyl or aralkyl halide or mesylate in thepresence of a base, e.g. sodium hydride. The reaction is carried outunder anhydrous conditions in a hydrocarbon solvent, for example, drytoluene at reflux temperature for about 10 to 72 hours in an inertatmosphere, for example, nitrogen. This method is outlined below:##STR5##

In the above method, substitution of an equimolar ratio of adibromoalkane in place of an alkyl halide givesBis-N-azacycloalkan-2-onyl alkane.

Alternatively, a lactone of an alkanoic acid may be heated with analkyl, aryl or aralkyl amine (with or without solvent) for about 20 to72 hours at about 180°-250° C. with removal of water to obtain thecorresponding 1-substituted azacycloalkan-2-one as shown below: ##STR6##

Similarly, heating a lactone of an alkanoic acid with a diaminoalkane ina 2.5 to 1 molar ratio gives the bis-N-azacycloalkan-2-onyl alkane.

In another method gamma-dialkylaminobutyric acid may be treated withphosphorous trihalide and the resulting acid halide (which need not beisolated) is heated, resulting specifically in the formation ofN-alkylazacyclopentan-2-one. Suitable acid halide forming agents includephosphorous trichloride, phosphorous tribromide, thionyl chloride, etc.The acid halide is formed at room temperature and then the reactiontemperature is raised to 70°-90° C. One of the alkyl groups on the aminonitrogen of the parent acid is eliminated as alkyl halide. If the alkylgroups on the amino nitrogen are different, the smaller of the two alkylgroups is eliminated preferentially. This method is described below.##STR7##

The amount of 1-substituted azacycloalkan-2-one which may be used in thepresent invention is an effective, non-toxic amount for enhancingpercutaneous absorption. Generally, this amount ranges between about0.01 to about 5 and preferably about 0.1 to 2 percent by weight of thecomposition.

The subject compositions may find use with many physiologically activeagents which are soluble in the vehicles disclosed.

Fungistatic and fungicidal agents such as, for example, thiabendazole,chloroxine, amphotericin, candicidin, fungimycin, nystatin,chlordantoin, clotrimazole, ethonam nitrate, miconazole nitrate,pyrrolnitrin, salicylic acid, fezatione, ticlatone, tolnaftate,triacetin and zinc and sodium pyrithione may be dissolved in thevehicles described herein and topically applied to affected areas of theskin. For example, fungistatic or fungicidal agents so applied arecarried through the stratum corneum, and thereby successfully treatfungus-caused skin problems. These agents, thus applied, not onlypenetrate more quickly than when applied in the vehicles of the priorart, but additionally enter the animal tissue in high concentrations andare retained for substantially longer time periods whereby a far moresuccessful treatment is effected.

For example, the subject composition may also be employed in thetreatment of fungus infections on the skin caused by candida anddermatophytes which cause athletes foot or ringworm, by dissolvingthiabendazole or similar antifungal agents in one of the vehicles andapplying it to the affected area.

The subject compositions are also useful in treating skin problems, suchas for example, herpes simplex, which may be treated by a solution ofiododeoxyuridine dissolved in one of the vehicles, or such problems aswarts which may be treated with agents such as podophylline dissloved inone of the vehicles. Skin problems such as psoriasis may be treated bytopical application of a solution of a conventional topical steroid inone of the vehicles or by treatment with theophylline or antagonists ofβ-adrenergic blockers such as isoproterenol in one of the vehicles.Scalp conditions such as alopecia areata may be treated more effectivelyby applying steroids such as triamcinolone acetonide dissolved in one ofthe vehicles of this invention directly to the scalp.

The subject compositions are also useful for treating mild eczema, forexample, by applying a solution of fluocinolone acetonide or itsderivatives; hydrocortisone, triamcinolone acetonide, indomethacin, orphenylbutazone dissolved in one of the vehicles to the affected area.

Examples of other physiologically active steroids which may be used withthe vehicles include corticosteroids such as, for example, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorsone diacetate,flurandrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and its esters, chloroprednisone, clocortelone,descinolone, desonide, dexamethasone, dichlorisone, difluprednate,flucloronide, flumethasone, flunisolide, fluocinonide, flucortolone,fluoromethalone, fluperolone, fluprednisolone, meprednisone,methylmeprednisolone, paramethasone, prednisolone and prednisone.

The subject compositions are also useful in antibacterial chemotherapy,e.g. in the treatment of skin conditions involving pathogenic bacteria.Typical antibacterial agents which may be used in this invention includesulfonomides, penicillins, caphalosporins, penicillinase, erythromycins,lincomycins, vancomycins, tetracyclines, chloramphenicols,streptomycins, etc. Typical examples of the foregoing includeerythromycin, erythromycin ethyl carbonate, erythromycin estolate,erythromycin glucepate, erythromycin ethylsuccinate, erythromycinlactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline,demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline,etc.

The subject compositions are also useful in protecting ultra-sensitiveskin or even normally sensitive skin from damage or discomfort due tosunburn. Thus, dermatitis actinica may be avoided by application of asunscreen, such as para-aminobenzoic acid or its well-known derivativesdissolved in one of the vehicles, to skin surfaces that are to beexposed to the sun; and the protective para-aminobenzoic acid or itsderivatives will be carried into the stratum corneum more successfullyand will therefore be retained even when exposed to water or washing fora substantially longer period of time than when applied to the skin inconventional vehicles. This invention is particularly useful forordinary suntan lotions used in activities involving swimming becausethe ultraviolet screening ingredients in the carriers of the prior artare washed off the skin when it is immersed in water.

The subject compositions may also find use in treating scar tissue byapplying agents which soften collagen, such as aminoproprionitrile orpenecillamine dissolved in one of the vehicles of this inventiontopically to the scar tissue.

Agents normally applied as eye drops, ear drops, or nose drops are moreeffective when dissolved in the vehicles of this invention.

Agents used in diagnosis may be used more effectively when applieddissolved in one of the vehicles of this invention. Patch tests todiagnose allergies may be effected promptly without scratching the skinor covering the area subjected to an allergen when the allergens areapplied in one of the vehicles of this invention.

The subject compositions are also useful for topical application ofcosmetic or esthetic agents. For example, compounds such asmelanin-stimulating hormone (MSH) or dihydroxy acetone and the like aremore effectively applied to skin to simulate a suntan when they aredissolved in one of the vehicles of this invention. The agent is carriedinto the skin more quickly and in greater quantity when applied inaccordance with this invention. Hair dyes also penetrate more completelyand effectively when dissolved in one of the vehicles of this invention.

The effectiveness of such topically applied materials as insectrepellants or fragrances, such as perfumes and colognes, can beprolonged when such agents are applied dissolved in one of the vehiclesof this invention.

It is to be emphasized that the foregoing are simply examples ofphysiologically active agents including therapeutic and cosmetic agentshaving known effects for known conditions, which may be used moreeffectively for their known properties in accordance with thisinvention.

In addition, the vehicles of the present invention may also be used toproduce therapeutic effects which were not previously known. That is, byuse of the vehicles described herein, therapeutic effects heretofore notknown can be achieved.

As an example of the foregoing, griseofulvin is known as the treatmentof choice for fungus infections of the skin and nails. Heretofore, themanner of delivery of griseofulvin has been oral. However, it has longbeen known that oral treatment is not preferred because of side effectsresulting from saturation of the entire body with griseofulvin and thefact that only the outer layers of affected skin need to be treated.Therefore, because fungal infections are generally infections of theskin and nails, it would be advantageous to utilize griseofulvintopically. However, despite a long-felt need for a topical griseofulvin,griseofulvin has been used orally to treat topical fungus conditionsbecause there was not heretofore known any formulation which could bedelivered topically which would cause sufficient retention ofgriseofulvin in the skin to be useful therapeutically.

However, it has now been discovered that griseofulvin, in a range oftherapeutic concentrations between about 0.1% and about 10% may be usedeffectively topically if combined with one of the vehicles describedherein.

As a further example, acne is the name commonly applied to anyinflammatory disease of the sebaceous glands; also acne vulgaris. Themicroorganism typically responsible for the acne infection isCorynebacterium acnes. Various therapeutic methods for treating acnehave been attempted including topical antibacterials, e.g.hexachlorophene, and systemic antibiotics such as tetracycline. Whilethe systemic antibiotic treatment are known to be partially effective,the topical treatments are generally not effective.

It has long been known that systemic treatment of acne is not preferredbecause of side effects resulting from saturation of the entire bodywith antibiotics and the fact that only the affected skin need bytreated. However, despite a long-felt need for a topical treatment foracne, antibiotics generally have been used only systemically to treatacne because there was not heretofore known an antibacterial formulationwhich could be used topically which would be effective therapeuticallyin the treatment of acne. However, it has now been discovered thatantibiotics, especially those of the lincomycin and erythryomycinfamilies of antibiotics, may be used in the treatment of acne topicallyif combined with one of the vehicles described herein.

The antibiotics composition so applied is carried into and through theepidermis and deeper layers of the skin as well as into follicles andcomedones (sebum-plugged follicles which contain C. acnes) intherapeutically effective amounts and thereby successfully may be usedto temporarily eliminate the signs and symptoms of acne.

The term "physiologically active agent" is used herein to refer to abroad class of useful chemical and therapeutic agents includingphysiologically active steroids, antibiotics, anti-fungal agents,antibacterial agents, antineoplastic agents, allergens, antihistaminicagents, anti-inflammatory agents, ultraviolet screening agents,diagnostic agents, perfumes, insect repellants, hair dyes, etc.

Dosage forms for topical application may include solution nasal sprays,lotions, ointments, creams, gels, suppositories, sprays, aerosols andthe like. Typical inert carriers which make up the foregoing dosageforms include water, acetone, isopropyl alcohol, freons, ethyl alcohol,polyvinyl pyrrolidone, propylene glycol, fragrances, gel-producingmaterials, mineral oil, stearyl alcohol, stearic acid, spermaceti,sorbitan monooleate, "Polysorbates", "Tweens", sorbital,methylcellulose, etc.

The amount of the composition, and thus of the physiologically activeagent therein, to be administered will obviously be an effective amountfor the desired result expected therefrom. This, of course, will beascertained by the ordinary skill of the practioner. Due to enhancedactivity which is achieved, the dosage of agent may often be decreasedfrom that generally applicable. In accordance with the usual prudentformulating practices, a dosage near the lower end of the useful rangeof the particular agent may be employed initially and the dosageincreased as indicated from the observed response, as in the routineprocedure of the physician.

The examples which follow illustrate the vehicles and the compositionsof the present invention. Temperatures are given in degrees Centigrade.All reactions involving sodium hydride were carried out in an inertnitrogen atmosphere.

EXAMPLE 1 Preparation of 1-n-Hexylazacyclopentan-2-one having thefollowing structure: ##STR8##

13.7 g of 50% sodium hydride-mineral oil dispersion (6.85 g NaH, 0.285M) was placed in a 1 liter flask equipped with an addition funnel,condenser and a mechanical stirrer. This was washed with 2×100 ml ofpetroleum ether and the petroleum ether was decanted. About 250 ml ofdry toluene was then added and to this stirred mixture was addeddropwise a solution of 20.35 g (0.239 M) of azacyclopentan-2-one in 100ml of dry toluene. Upon completion of addition the mixture was heated toreflux for 1 hour and then cooled to room temperature. A solution of43.6 g (0.264 M) of 1-bromohexane in 100 ml of dry toluene was addeddropwise for a period of one-half hour and thereafter the mixture wasrefluxed for 48 hours. After cooling to room temperature, the reactionmixture was filtered and the filter cake was washed with dry toluene.The combined filtrate was concentrated to a yellow oil. Distillationgave 25.7 g (63.5%) of colorless 1-n-Hexylazacyclopentan-2-one, boilingpoint 98°-102°/0.5 mm.

EXAMPLE 2 Preparation of 1-n-Heptylazacyclopentan-2-one having theformula: ##STR9##

Following example 1, on refluxing 13 g of 50% oil dispersion of sodiumhydride (6.5 g NaH, 0.271 M), 20.35 g (0.239 M) of azacyclopentan-2-oneand 47.28 g (0.264 M) of 1-bromoheptane in dry toluene for 21 hours wasobtained 13.6 g (31%) of colorless oil; boiling point 115°-120°/0.6 mm.

EXAMPLE 3 Preparation of 1-n-Octylazacyclopentan-2-one ##STR10##

Following example 1, from 5.44 g of 57% oil dispersion of sodium hydride(3.10 g NaH, 0.13 M), 10 g (0.1174 M) of azacyclopentan-2-one and 25.1 g(0.13 M) of 1-bromooctane was obtained 13.6 g (59%) of colorless1-n-Nonylazacyclopentan-2-one. B.P. 123°-132°/0.3 mm.

EXAMPLE 4 Preparation of 1-n-Nonylazacyclopentan-2-one having theformula: ##STR11##

Following example 1, from 5.44 g of 57% sodium hydride-mineral oildispersion (3.10 g NaH, 0.13 M), 10 g (0.1174 M) of azacyclopentan-2-oneand 27 g (0.13 M) of 1-bromononane was obtained 13.4 g (56%) of1-n-Nonylazacyclopentan-2-one, b.p. 139°-143°/0.5 mm.

EXAMPLE 5 Preparation of 1-n-Decylazacyclopentan-2-one having theformula ##STR12##

18.8 g (0.22 M) of γ-butyrolactone and 34.6 g (0.22 M) of n-decylaminewere mixed and heated to 180° in a round bottom flask equipped with acondenser and a Dean-Stark trap for 22 hours. The dark brown reactionmixture was distilled at reduced pressure to yield 40.9 g (82.5%) ofcolorless product; b.p. 150°-155°/0.5-1 mm.

EXAMPLE 6 Preparation of n-Dodecylazacyclopentan-2-one having theformula ##STR13##

Following example 5, 18.8 g (0.22 M) of γ-butyrolactone and 37 g (0.2 M)of n-dodecylamine was heated for 24 hours. Distillation of the residuegave 40.7 g (80.3%) of 1-n-Dodecylazacyclopentan-2-one; b.p.165°-170°/0.5 mm.

EXAMPLE 7 Preparation of 1-Methylazacycloheptan-2-one having the formula##STR14##

A suspension of 8.42 g of 57% sodium hydride-mineral oil suspension (4.8g NaH, 0.2 M) was washed with 2×400 ml portions of dry toluene and thetoluene washings were decanted. 350 ml of dry toluene was added and thesuspension was mechanically stirred while a solution of 20 g (0.177 M)of azacycloheptan-2-one in 50 ml of dry toluene was added dropwise over1 hour. After the addition was over, the mixture was refluxed for 1 hourand then cooled to room temperature. 22.0 g (0.2 M) of methyl mesylatewas added dropwise over 1 hour and the reaction mixture was then warmedto 50° for 1 hour. The mixture was cooled, filtered and the filter cakewas resuspended in 100 ml of dry toluene and filtered. The combinedfiltrate was concentrated and the residue was distilled to yield 20 g(88.85%) of 1-Methylazacycloheptan-2-one; b.p. 85°-87°/0.1 mm.

EXAMPLE 8 Preparation of 1-n-propylazacycloheptan-2-one having theformula ##STR15##

In a 1 liter 3-neck flask equipped with a dry ice-isopropanol condenser,an addition funnel and a mechanical stirrer was placed 10.2 g of 50%sodium hydride-mineral oil disperson (5.1 g NaH, 0.2125 M) and 150 ml ofpetroleum ether. Thus suspension was momentarily stirred and then sodiumhydride was allowed to settle. Most of the petroleum ether was pipettedout and 200 ml of dry toluene was added. To this was added dropwise asolution of 20 g (0.177 M) of azacycloheptan-2-one in 100 ml of drytoluene. The mixture was refluxed for 1 hour and then cooled to roomtemperature. A solution of 30.75 g (0.25 M) of 1-bromopropane in 100 mlof dry toluene was added dropwise under stirring. Upon completion of theaddition, the mixture was warmed to 80°-100° and the temperature wasmaintained there for 4 hours. Then the isopropanol-dry ice condenser wasreplaced with a water condenser and the reaction mixture was heated toreflux for 15 hours. The reaction mixture was cooled, filtered and thefiltrate was concentrated to a yellow oil. Distillation afforded 22.2 g(81%) of colorless product; b.p. 83°-86° /0.25 mm.

EXAMPLE 9 Preparation of 1-n-Butylazacycloheptan-2-one having theformula ##STR16##

Following example 8, from 12.75 g of 50% sodium hydride-mineral oildispersion (6.375 g NaH, 0.266 M), 25 g (0.221 M) ofazacycloheptan-2-one and 34.25 g (0.25 M) of 1-bromobutane was obtainedon 18 hr. reflux 26.8 g (72%) of colorless product; b.p. 95°-100°/0.3mm.

EXAMPLE 10 Preparation of 1-Pentylazacycloheptan-2-one having theformula ##STR17##

Following example 8 and using water condenser from the start of thereaction, 10 g of 50% sodium hydride-mineral oil dispersion (5 g NaH,0.21 M), 20 g (0.177 M) of azacycloheptan-2-one and 30.2 g (0.2 M) of1-bromopentane on 18 hr. reflux gave 23.3 g (87%) of colorless product;b.p. 110°-115°/0.3 mm.

EXAMPLE 11 Preparation of 1-n-Hexylazacycloheptan-2-one having theformula ##STR18##

Following example 10, from 10.2 g of 50% sodium hydride-mineral oildispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-oneand 33 g (0.2 M) of 1-bromohexane on 19 hr. reflux was obtained 29.8 g(85.3%) of colorless product; b.p 122-128°/0.4 mm.

EXAMPLE 12 Preparation of 1-n-Heptylazacycloheptan-2-one having theformula ##STR19##

Following example 10, 10.2 g of 50% sodium hydride-mineral oildispersion (15.1 g of NaH, 0.2125 M), 20 g (0.177 M) ofazacycloheptan-2-one and 35.8 g (0.2 M) of 1-bromoheptane on 18 hr.reflux gave 33.5 g (90%) of colorless product; b.p. 155°-158°/0.5 mm.

EXAMPLE 13 Preparation of 1-n-Octylazacycloheptan-2-one having theformula ##STR20##

Following example 5, heating 17.5 g (0.153 M) of 6-hexanolactone and 22g (0.17 M) of 1-aminooctane at 180° for 29 hr. gave 8.8 g (27%) ofproduct; b.p. 155°-160°/0.5 mm.

EXAMPLE 14 Preparation of 1-n-Nonylazacycloheptan-2-one having theformula ##STR21##

Following example 5, heating 22.83 g (0.2 M) of 6-hexanolactone and28.65 g (0.2 M) of 1-aminononane at 180° for 20 hours gave 11.5 g (26%)of product; b.p. 155°-165°/0.6 mm.

(Higher yields of 1-n-Octyl- and 1-n-Nonylazacycloheptan-2-one may beobtained by use of the sodium hydride method).

EXAMPLE 15 Preparation of 1-n-Decylazacycloheptan-2-one having theformula ##STR22##

Following example 10, 10.2 g of 50% sodium hydride-mineral oildispersion (5.1 g NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-oneand 44.2 g (0.2 M) of 1-bromodecane on 19 hr. reflux gave 38 g (84.7%)of product; b.p. 158°-163 °/0.25-0.3 mm.

EXAMPLE 16 Preparation of 1-n-Dodecylazacycloheptan-2-One having theformula ##STR23##

Following example 10, 15.3 g of 50% sodium hydride-mineral oildispersion (7.65 g NaH, 0.319 M), 30 g (0.266 M) of azacycloheptan-2-oneand 66.1 g (0.265 M) of 1-bromododecane on 20 hr. reflux gave 60 g (80%)of colorless product; b.p. 175°-180°/0.3 mm.

EXAMPLE 17 Preparation of 1-n-Butylazacyclononan-2-one having theformula ##STR24##

Following example 10, 16.32 g of 50% sodium hydride-mineral oildispersion (8.16 g NaH, 0.34 M), 40 g (0.283 M) of azacyclononan-2-oneand 43 g (0.311 M) of 1-bromobutane was refluxed for 22 hours. Thereaction mixture was diluted with benzene-tolune and was extracted withwater. The organic phase was separated, dried and concentrated to ayellow oil. Distillation afforded 41.4 g (74%) of product; b.p.166°-170°/0.2 mm.

EXAMPLE 18 Preparation of 1-n-Octylazacyclononan-2-one having theformula ##STR25##

Following example 17, 4.2 g of 50% sodium hydride-mineral oil dispersion(2.1 g NaH, 0.0875 M), 10 g (0.0708 M) of azacyclononan-2-one and 15 g(0.0777 M) of 1-bromooctane gave 12.5 g (70%) of product; b.p.150°-160°/0.5 mm.

EXAMPLE 19 Preparation of 1-Phenylazacyclopentan-2-one having theformula ##STR26##

9.3 g (0.1 M) of aniline and 9.5 g (0.11 M) of γ-butyrolactone weremixed and heated to 200° for 48 hours. At the end of the reaction,unreacted starting materials and water were removed at reduced pressure.Distillation of the residue gave 6.3 g (39%) of the product (89% yieldbased on reclaimed aniline); b.p. 138°-140°/0.3 mm. Yield in thisreaction can be improved if the water formed during the reaction isseparated out with or without the use of a solvent (benzene or toluene).

EXAMPLE 20 Preparation of 1-Benzylazacyclopentan-2-one having theformula ##STR27##

6.97 g (0.06 M) of γ-butyrolactone is mixed with 6.97 g (0.065 M) ofbenzylamine and heated at 190° for 24 hours. Excess benzyl amine andwater was distilled off and the residue was distilled to obtain 7.4 g(70%); b.p. 125°-130°/1 mm.

EXAMPLE 21 Preparation of 1-(2-chlorophenyl)azacyclopentan-2-one havingthe formula ##STR28##

Following example 19, 12.57 g (0.1 M) of 2-chloroaniline and 9.5 g (0.11M) of γ-butyrolactone were heated for 48 hours. The excess stargingmaterials were removed at 50°-80°/0.3 mm. Distillation of the residuegave 4.9 g (25%) of product (45% based on recovered 2-chloroaniline);b.p. 150°-155°/0.3-0.4 mm.

EXAMPLE 22 Preparation of 1,3-Bis(1-azacyclopentan-2-onyl) propanehaving the formula ##STR29##

To 11.0 g of 57% sodium hydride-mineral oil suspension (6.27 g NaH,0.261 M) was added 150 ml of dry toluene and this was stirred for a fewminutes. Toluene was decanted and 150 ml of fresh dry toluene was added.20 g (0.235 M) of azacyclopentan-2-one was added dropwise over 1 hourand after the addition was over the mixture was refluxed for 1 hour.22.3 g (0.11 M) of 1,3-dibromopropane was added dropwise over threehours. The refluxing was continued for 72 hours and then the reactionmixture was cooled and filtered twice, the second time through celite.The filtrate was concentrated and the residue was distilled to obtain8.2 g (35.4%) of product; b.p. 170°-180°/0.03 mm.

EXAMPLE 23 Preparation of 1,6-Bis-(1-azacyclopentan-2-onyl) hexanehaving the formula ##STR30##

11.62 g (0.1 M) of 1,6-diaminohexane and 21.66 g (0.25 M) of65-butyrolactone were mixed and heated to 150°-165° for 22 hours. Excessγ-butyrolactone was then distilled off at reduced pressure (80°/2 mm).The light brown residue was poured into a crystallization dish where itimmediately solidified. The solid was taken in chloroform, powdered,filtered and the tan powder was washed with chloroform. Yield 22.0 g(87%); melting point 101°-103°.

EXAMPLE 24

The following solution formulation is prepared:

    ______________________________________                                                           Solution (%)                                               ______________________________________                                        Griseofulvin         1                                                        1-n-dodecylazacycloheptan-2-one                                                                    1                                                        Isopropyl myristate  5                                                        Fragrance            0.1                                                      Ethanol              92.9                                                     ______________________________________                                    

This formulation is effective in the treatment of fungus infections.

EXAMPLE 25

An aerosol form of the formulation of Example 24 is prepared bypreparing the following mixture:

    ______________________________________                                               Formulation 25%                                                               Freon.sup.1 75%                                                        ______________________________________                                         .sup.1 Freon is 75/25 Freon 114/12.                                      

EXAMPLE 26

The following cream formulation is prepared:

    ______________________________________                                                            %                                                         ______________________________________                                        Clindamycin (base     1.0                                                     Stearyl alcohol, U.S.P.                                                                             12.0                                                    Ethoxylated cholestrol                                                                              0.4                                                     Synthetic spermaceti  7.5                                                     Sorbitan monooleate   1.0                                                     Polysorbate 80, U.S.P.                                                                              3.0                                                     1-n-dodecylazacycloheptan-2-one                                                                     0.5                                                     Sorbitol solution, U.S.P.                                                                           5.5                                                     Sodium citrate        0.5                                                     Chemoderm #844 Fragrance                                                                            0.2                                                     Purified water        68.4                                                    ______________________________________                                    

This formulation is effective in the treatment of acne.

EXAMPLE 27

The following solution formulations are prepared:

    ______________________________________                                                          A(%)    B(%)                                                ______________________________________                                        Clindamycin base    --        1.0                                             Clindamycin phosphate acid                                                                        1.3       --                                              Sodium hydroxide    0.077     --                                              1.0 Molar hydrochloric acid                                                                       --        2.27                                            Disodium edetate . 2H.sub.2 O                                                                     0.003     0.003                                           Fragrances          0.5       0.5                                             1-n-dodecylazacycloheptan-2-one                                                                   1.0       1.0                                             Purified water      20.0      17.73                                           Isopropanol         77.12     77.497                                          ______________________________________                                    

These solutions are effective for the treatment of acne in humans.

EXAMPLE 28

The following solution formulation is prepared:

    ______________________________________                                                            %                                                         ______________________________________                                        Neomycin sulfate      0.5                                                     Lidocaine             0.5                                                     Hydrocortisone        0.25                                                    1-n-dodecylazacycloheptan-2-one                                                                     0.5                                                     Propylene glycol      98.25                                                   ______________________________________                                    

This solution is effective for the treatment of otitis in domesticanimals.

EXAMPLE 29

The following sunscreen emulsion is prepared:

    ______________________________________                                                            %                                                         ______________________________________                                        p-amino benzoic acid  2.0                                                     Benzyl alcohol        0.5                                                     1-n-dodecylazacycloheptan-2-one                                                                     1.0                                                     Polyethylene glycol 500-MS                                                                          10.0                                                    Isopropyl lanolate    3.0                                                     Lantrol               1.0                                                     Acetylated lanolin    0.5                                                     Isopropyl myristate   5.0                                                     Light mineral oil     8.0                                                     Cetyl alcohol         1.0                                                     Veegum                1.0                                                     Propylene glycol      3.0                                                     Purified water        64.0                                                    ______________________________________                                    

EXAMPLE 30

The following antineoplastic solution is prepared:

    ______________________________________                                                            %                                                         ______________________________________                                        5-Fluorouracil        5                                                       1-n-dodecylazacycloheptan-2-one                                                                     0.1                                                     Polyethylene glycol   5                                                       Purified water        89.9                                                    ______________________________________                                    

EXAMPLE 31

The following insect repellant atomizing spray is prepared:

    ______________________________________                                                            %                                                         ______________________________________                                        Diethyltoluamide      0.1                                                     1-n-dodecylazacycloheptan-2-one                                                                     0.1                                                     Ethanol               99.8                                                    ______________________________________                                    

EXAMPLE 32

The following lotion formulation may be prepared containing about 0.001to 1 percent, with preferably 0.1 percent fluocinolone acetonide:

    ______________________________________                                                            %                                                         ______________________________________                                        Fluocinolone acetonide                                                                              0.001-1                                                 Cetyl alcohol         15                                                      Propylene glycol      10                                                      Sodium lauryl sulfate 15                                                      1-n-dodecylazacycloheptan-2-one                                                                      1                                                      Water (to make 100%)                                                          ______________________________________                                    

The steroid is dissolved in the vehicle and added to a stirred, coolingmelt of the other ingredients. The preparation is particularly usefulfor the treatment of inflammed dermatoses by topical application to theaffected skin area. The amount and frequency of application is inaccordance with standard practice for topical application of thissteroid. Penetration of the steroid into the inflammed tissue isenhanced and a therapeutic level is achieved more rapidly and sustainedfor longer duration than when the steroid is applied in conventionalformulations.

EXAMPLE 33

Examples 24-32 are repeated, except the 1-n-dodecylazacycloheptan-2-oneis replaced with an equal amount of each of the following compounds:

1-n-hexylazacyclopentan-2-one

1-n-heptylazacyclopentan-2-one

1-n-octylazacyclopentan-2-one

1-n-nonylazacyclopentan-2-one

1-n-decylazacyclopentan-2-one

1-n-dodecylazacyclopentan-2-one

1-methylazacycloheptan-2-one

1-n-propylazacycloheptan-2-one

1-n-butylazacycloheptan-2-one

1-n-pentylazacycloheptan-2-one

1-n-hexylazacycloheptan-2-one

1-n-heptylazacycloheptan-2-one

1-n-octylazacycloheptan-2-one

1-n-nonylazacycloheptan-2-one

1-n-decylazacycloheptan-2-one

1-n-butylazacyclononan-2-one

1-n-octylazacyclononan-2-one

1-phenylazacyclopentan-2-one

1-benzylazacyclopentan-2-one

1-(2-chlorophenyl)azacyclopentan-2-one

1,3-Bis-(1-azacyclopentan-2-onyl)propane

1,6-Bis-(1-azacyclopentan-2-onyl)hexane

Comparable results are obtained.

I claim:
 1. A composition useful for topically administering aphysiologically active agent to a human or animal comprising aneffective amount of a physiologically active agent and a nontoxic,effective penetrating amount of a compound having the structural formula##STR31## wherein n is 0-11 and R' is H or a lower alkyl group having1-4 carbon atoms.
 2. The composition of claim 1 wherein thephysiologically active agent is an antibacterial agent.
 3. Thecomposition of claim 1 wherein the antibacterial agent is an antibiotic.4. The composition of claim 3 wherein the antibiotic is selected fromthe group consisting of lincomycin, clindamycin, erthromycin andpharmaceutically useful salts thereof.
 5. The composition of claim 1wherein the physiologically active agent is a physiologically activesteroid.
 6. The composition of claim 1 wherein the physiologicallyactive agent is an antifungal agent.
 7. The composition of claim 1wherein the physiologically active agent is iododeoxyuridine.
 8. Thecomposition of claim 1 wherein the physiologically active agent is5-fluorouracil.
 9. A composition comprising an effective amount of aphysiologically active agent and an effective, penetrating amount of acompound having the structural formula ##STR32## where R' is H or alower alkyl group having 1-4 carbon atoms, n is 0-17 and R is --CH₃ or##STR33## where R" is H or halagen.
 10. A composition for topicallyadministering a physiologically active agent to a human or animalcomprising an effective amount of a physiologically active agent and anon-toxic, effective penetrating amount of1-n-dodecylazacycloheptan-2-one.
 11. A composition comprising aneffective amount of physiologically active agent and an effective,penetrating amount of 1-n-dodecylazacycloheptan-2-one.